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Incorporation
of
Viral
DNA
in
to
the
Genome
of
the
Host |
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Incorporation
of
Viral
DNA
in
to
the
Genome
of
the
Host - A virus usually multiplies in specific cells derived from animals in which the virus normally grows. Such cells are called permissive cells.
Cells in which viruses do not grow are called non permissive cells.
Viruses on entering host cells undergo one of the two types of behaviour.
(i) They enter the lytic phase and multiply within the host cells, ultimately killing them. This type of infection is called lytic infection or productive infection, e. g, in a adenoviruses.
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(ii) The viral DNA maybe inserted into the DNA of host chromosomes, and becomes an integral part of host DNA. The virus is now said to become a provirus.
Transformation be normal cells into cancerous cells is often due to integration of viral genes into the chromosomes of the host cells, The gene of a cancer causing virus which is responsible for transformation is called an oncogene
Carcinogens Agents which cause cancers are called carcinogens. It is believed that carcinogens affect the natural genetic processes of cells and disturb the control mechanisms.
Carcinomas were produced on the ears of rabbits by painting them with coal tar (Yamagiwa and Itchikawa, 1912). The active agent was later identified as 3,4-benzapyrene.
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The carcinomas continued to grow even when the Jar was removed, indicating that once a carcinogen induces cellular abnormality its presence is
not necessary to continue that abnormality.
Various forms of radiations are sources of cancer. Thus exposure of the thyroid gland to X-rays greatly increases the incidence of thyroid cancers.
A large number of chemical compounds have been proved to be
carcinogenic to man.
Heidelberg (1975) writes: "The overall conclusion from modern epidemiology is that 80-90 per cent of all cancers are environmentally caused. Of these, chemicals are the predominant carcinogens. Many chemical carcinogens become covalently bound to DNA, RNA and proteins, and probably induce cancer.
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There are several problems regarding the cellular mechanism of chemical carcinogenesis.
(1) Do chemical carcinogens directly transform cells to malignancy or do they select pre existing malignant cells?
Experiments on transformation of hamster embryo cells and mouse fibroblasts suggest that transformation is direct.
(2). Do chemicals transform cells directly or is transformation caused indirectly by activating oncogenic viruses already present in the cell?
At least in some cases chemicals have been found to directly transform cells.
3. Is the chemical transformation mechanism a mutagenic one involving DNA sequences, or one involving gene expression?
Chemical transformation is widely considered to be a mutagenic one.
There is chemical interaction of chemical oncogens, possibly with DNA, resulting in the alteration of the primary sequence of DNA.
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However, it has also been suggested that cancers could result from abornal differentiation involving alteration of gene expression, e. g. from interaction of carcinogen with repressor protein.
Many chemical carcinogens may not have direct mutagenic activity.
On entering the cells, however, the carcinogens are chemically transformed into derivatives that may be more carcinogenic than their precursors, for example, nitrates are not carcinogenic or mutagenic but may become converted to nitrosamines which are powerful mutagens and carcinogens.
It has been stated that most carcinogenesis is the result of changes in DNA.
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Among the most carcinogenic substances known are nitrosamines. They are suspected to be the major causative agents of human cancer.
Any secondary amine on reaction with nitrous acid forms a nitrosamine.
Absorption of nitrosamines from the stomach could result in cancer in various organs. All plants contain nitrates which could be reduced to nitrites.
Many meats contain both nitrates and nitrites. The nitrite could react with secondary amines in the stomach to product nitrosamines.
Secondary amines are found in many drugs and natural foods.
What is the mechanism by which carcinogens induce cancers ?
1. Accumulation of mutational defects brought about by carcinogens:Carcinogens may cause alterations in DNA (mutations). Several mutational defects may result in the cell becoming cancerous (multi-hit-initiation )
2. Repression of normal gene activities. Carcinogens or their reactive metabolic derivatives may bind with DNA and cause disorganisation in the decoding of DNA information.
This may bring' about repression of certain normal gene activities in precancerous cells.
Repression could also take place by combination with products of genes e. g. enzymes, rather than the genes themselves. Both these activities are not somatic mutations, since the DN itself is not altered
3 Derepression of forbidde gene activities.
Carcinogens may induce ‘forbidden gene’ 'transcriptions for enzymes that stimulate cell division.
This is brought about by derepression of certain information in DNA that is normally repressed. Probably the most acceptable suggestion of how transformation occurs is that the products of viral genes derepress extensive regions of the cellular genome.
Oncogene theory:Huebner and Todaro (1969, 1972) have proposed their 'oncogene theory' according to which all cells carry the genetic information for malignancy, and, in most cases; for cancer generating viruses (oncogenic viruses).
According to the hypothesis carcinogens 'switch on' oncogenic viruses that cause transformation of normal cells into malignant cells.
There is considerable chemical evidence for this oncornaviruses have been found in a number of chemically induced tumours.
However it is not known whether the viruses actually cause these turn ours or whether they are harmless passengers.
Experiments were carried out by Freeman et al (1971) on cell cultures of hamster embryo cells lines.
Cells which were negative for infectious oncornaviruses after transformation by chemicals were inoculated into hamsters. They produced tumours hat contained oncornaviruses.
It was concluded that chemical treatments and activation pf the virus were related events.
However, there is also evidence to the contrary.
In several clones of cells (from embryos of inbred mice) transformed to malignancy with chemicals, there was no evidence of the infectious viruses.
This indicates that there is no switching on of complete transforming viruses in chemical oncogenic transformation.
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